Cardiovascular disease accounts for nearly one third of deaths globally, and coronary artery disease remains the number one cause of death in the United States. Diabetes increases the risk of fatal CAD and peripheral vascular disease. Vascular smooth muscle cell (VSMC) proliferation and migration contribute to coronary artery disease and are the major causes of coronary artery in-stent restenosis and accelerated arteriopathy following cardiac transplantation. Drug-eluting stents (rapamycin-sirolimus) was a major advance in the treatment of CAD, causing significant reduction in the incidence of restenosis. However, diabetic patients still had a two-fold higher incidence of restenosis compared to non-diabetics. We will use rapamycin as a "molecular probe" to dissect pathways that govern VSMC growth and migration. Aim one will test the hypothesis that diabetes leads to an overstimulation of the PI3K/Akt/Foxo pathway', decreasing p27Kip1 gene expression, conferring relative rapamycin resistance. We will examine the effects of rapamycin on the proliferation and migration of VSMC grown in the presence of high glucose Jeptin treated, then on the formation of neointimal hyperplasia following arterial injury in different mouse models of diabetes. Aim two will determine whether blocking multiple growth pathways using rapamycin and inhibitors of Akt/PI3K can synergistically inhibit intimal proliferation following vascular injury in diabetic/obesity animal models. We will test new drug combinations in animal model in which resistance to rapamycin's antiproliferative effect was observed.